liver fibrosis model

Ischemia–Reperfusion Injury Model

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Model Introduction

In the research of hepatobiliary surgery, organ transplantation, and acute liver failure, ischemia-reperfusion injury (IRI) is a core topic. However, depending on the research objective (such as investigating hepatocyte regeneration, biliary obstruction injury, or chronic evolution), several classic models are often adopted in clinical and scientific research as supplements or alternatives to IRI studies:

  1. Partial Hepatectomy (PH) Model: As the preferred model for studying liver regeneration and acute liver injury. By resecting different proportions (30%, 70%, 90%) of liver lobes, it simulates liver tissue loss and compensatory growth after clinical hepatectomy, serving as the gold standard for evaluating liver repair capacity.
  2. Bile Duct Ligation (BDL) Model: Used to simulate obstructive jaundice and cholestatic liver injury. This model stably induces hepatocyte injury and subsequent fibrosis progression caused by increased biliary pressure, commonly used to study bile duct epithelial damage and inflammatory reactions.
  3. Chemical/Drug-Induced Injury Model: Utilizing carbon tetrachloride (CCl₄) or dimethylnitrosamine (DMN) to induce acute or chronic liver injury, simulating the cycle of cell necrosis and repair caused by hepatotoxic substances.
  4. Composite Injury Model: Combining a high-fat diet, alcohol gavage, and chemical induction to simulate the complex metabolic liver injury environment in humans, aligning more closely with multi-factorial clinical pathogenesis.

Research Applications

These alternative models are widely applied in the following fields:

  • Liver Regeneration Mechanism Research: Exploring the signaling pathways for hepatocytes entering the cell cycle and the roles of cytokines (e.g., HGF, TNF-α).
  • Organ Transplantation Prognosis Evaluation: Simulating the compensatory pressure and functional recovery of the remnant liver after liver transplantation.
  • Anti-fibrotic Drug Screening: Utilizing BDL or CCl₄ models to evaluate drug inhibition of hepatic stellate cell (HSC) activation and collagen deposition.
  • Acute Liver Failure Treatment Exploration: Establishing a 90% extreme hepatectomy model to study interventions for reducing mortality rates.
  • NAFLD/ALD Research: Simulating pathological evolution from steatosis and inflammation to fibrosis.

Key Points of Experimental Design

To ensure the scientific validity and reproducibility of the models, experimental design must focus on the following core aspects:

  1. Animal Selection: Priority is given to mice (clear genetic background, easy to obtain) or rats (large surgical space, distinct fibrosis staging).
  2. Surgical Precision:
    • PH Model: Requires skilled ligation of the hepatic pedicle to ensure precise resection proportions (e.g., a 70% model requires resection of the left lateral and median lobes).
    • BDL Model: Double ligation of the common bile duct with transection in between to ensure complete obstruction; strict aseptic operation is required to prevent peritonitis.
  3. Modeling Period Control:
    • Acute injury (e.g., PH, acute CCl₄) typically involves monitoring indicators within 24-72 hours.
    • Chronic fibrosis (e.g., BDL, long-term CCl₄) requires 2-8 weeks to observe pathological evolution.
  4. Ethics and Safety: For volatile and highly toxic reagents like DMN, protection for laboratory personnel must be strengthened; necessary analgesia and post-operative care must be provided.

Key Monitoring Indicators

  • Serum Biochemical Indicators:
    • Liver Injury Markers: ALT (Alanine aminotransferase), AST (Aspartate aminotransferase).
    • Cholestasis Indicators: Total bilirubin (TBIL), Alkaline phosphatase (ALP).
    • Metabolic Indicators: Triglycerides (TG), Total cholesterol (TC).
  • Histopathological Evaluation:
    • HE Staining: Observation of hepatocyte swelling, vacuolar degeneration, necrosis, and inflammatory cell infiltration.
    • Sirius Red/Masson Staining: Assessment of collagen fiber deposition and fibrosis grading (S0-S4).
  • Molecular Biological Indicators:
    • HSC Activation Markers: α-SMA, Col-I.
    • Inflammatory Cytokines: TNF-α, IL-6, Osteopontin.
  • Clinical Sign Observation: Changes in animal body weight, fur luster, activity, and urine color (e.g., dark tea-colored urine in BDL models).

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